Molecular and clinicopathologic characterization of pediatric histiocytoses

Abstract

The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAF V600E . Most BRAF WT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH).BRAF V600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAF V600E -mutated LCH case samples, NGS revealed mutations as follows:MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5).Wild-type sequences were identified in 17.1% of samples. BRAF V600E was the only variant significantly correlated with critical presentations: organ-risk involvement and Jean-François Emile and Sébastien Heritier contributed equally to this study.

Impact of BRAFV600E mutation on aggressiveness and outcomes in adult clonal histiocytosis

“…Our data showed that BRAF V600E mutation was associated with multicentric disease and risk organ involvement. This phenotype is in line with pediatric LCH ( 6 ) ( 7 ) studies and ECD cohort ( 8 ). Excluding RDD patients, the presence of BRAF V600E correlated with risk organ involvement irrespective of the type of “L-group histiocytosis”.…”

“…Interestingly the genetic landscape analysis of various cancers, such as melanoma, colon cancer, lung cancer, and more recently histiocytic neoplasms, has highlighted the pivotal role of BRAF V600E gene, which is considered an important cornerstone in the development of human cancer. Its presence is associated with disseminated disease, neurodegeneration, and resistance to front-line therapy in pediatric LCH patients ( 6 , 7 ). In adults, LCH is mainly restricted to the lung, making BRAF V600E testing difficult due to the risk of a pulmonary biopsy procedure and a low DNA quantity when available.…”

Frequent detection of genetic aberrations reveals novel pathogenesis and treatment modalities in systemic juvenile xanthogranuloma

“…In the past decade, genomic studies have been conducted on histiocytosis, including JXG, and distinctive genetic abnormalities have been discovered (e.g., BRAFV600E mutations and ALK translocations). 4 , 5 These novel genetic discoveries further confirmed the tumorigenesis of JXG and highlighted the possibility of therapeutic targets in refractory or severe cases.…”

Impact of molecular status on clinical management in children with histiocytosis treated according to POL HISTIO project

“…At the origin of these diseases is a clonal proliferation of cells that morphologically and immunophenotypically resemble macrophage line cells. Excessive activation of the RAS/ /mitogen-activated protein kinases (MAPK) signaling pathway lies at the base of the pathomechanism [2,4,5]. The current classification divides histiocytosis into five groups: C, H, L, M and R.…”

“…Therefore, the management of LCH can vary greatly from a 'wait-and-watch' attitude through serious procedures such as intensive chemotherapy up to bone marrow stem cell transplantation. In LCH, BRAF V600E is the most frequently detected mutation, followed by MAP2K1 alterations [1,2,5,7,8]. The occurrence of mutations seems to cause a more severe course and resistance to conventional chemotherapy, with potentially higher mortality and severe secondary conditions such as neurodegenerative disease (ND) or sclerosing cholangitis (SC) with consequent liver cirrhosis [7,[9][10][11][12].…”